EP1363902A1 - Chemische verbindungen - Google Patents

Chemische verbindungen

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Publication number
EP1363902A1
EP1363902A1 EP02711619A EP02711619A EP1363902A1 EP 1363902 A1 EP1363902 A1 EP 1363902A1 EP 02711619 A EP02711619 A EP 02711619A EP 02711619 A EP02711619 A EP 02711619A EP 1363902 A1 EP1363902 A1 EP 1363902A1
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Prior art keywords
alkyl
compound
alkoxy
optionally substituted
formula
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EP02711619A
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English (en)
French (fr)
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EP1363902B1 (de
Inventor
Stephen AstraZeneca R & D Charnwood BROUGH
Thomas AstraZeneca R & D Charnwood MCINALLY
Matthew AstraZeneca R & D Charnwood PERRY
Brian AstraZeneca R & D Charnwood SPRINGTHORPE
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AstraZeneca AB
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AstraZeneca AB
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A—HUMAN NECESSITIES
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to substituted piperidine compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif.
  • the chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C- C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP- 1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MlP-l ⁇ and MlP-l ⁇ ).
  • the present invention provides a compound of formula (I):
  • R 1 is phenyl which is optionally substituted by halogen, C alkyl, C haloalkyl, CM alkoxy, C ⁇ haloalkoxy, nitro or cyano;
  • R 2 , R 3 and R 4 are, independently, hydrogen or CM alkyl;
  • R 5 is C 1 -6 alkyl, aryl, heteroaryl, or C 3 . 8 cycloalkyl; wherein the aryl and heteroaryl moieties of R 5 are optionally substituted by halogen, Q. 6 alkyl (optionally substituted by halogen, C ⁇ .
  • X is (CH 2 )n, where n is 1, 2, 3 or 4;
  • Y is a 2,4-, 2,5- or 3,5- linking 5-membered heteroaryl ring comprising 2 or 3 heteroatoms independently selected from the group comprising nitrogen, oxygen and sulphur, wherein
  • Y is optionally substituted by C ⁇ alkyl
  • R 6 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are, independently, hydrogen or C1- 6 alkyl (optionally substituted by C ⁇ .
  • R 7 and R 11 are, independently, C ⁇ alkyl (optionally substituted by C ⁇ _ 6 alkoxy (provided no thioacetal is formed) or phenyl (itself optionally substituted by halogen, CM alkyl, C M alkoxy or CF 3 ));
  • R 12 is hydrogen, C ⁇ _ 6 alkyl (optionally substituted by C ⁇ . 6 alkoxy (provided no acetal is formed) or phenyl (itself optionally substituted by halogen, C M alkyl, C M alkoxy or CF 3 )) or C ⁇ - 6 alkoxy (unsubstituted or mono-substituted by C ⁇ . 6 alkoxy or phenyl (itself optionally substituted by halogen, C alkyl, CM alkoxy or CF 3 )); or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof.
  • the present invention encompasses all such isomers and mixtures thereof in all proportions.
  • the group Y is a 2,4- or 2,5-linked imidazolyl ring, oxazolyl or thiazolyl ring, a
  • Aryl is, for example, phenyl or naphthyl. In one aspect of the invention aryl is phenyl.
  • Heteroaryl is an aromatic, mono- or bi-cyclic ring system preferably comprising 1 , 2 or 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur.
  • Heteroaryl is, for example, imidazolyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-, 1,2,4- or 1,3,5-triazinyl, benzo[b]thienyl, benzo[b]furyl, indolyl or quinolinyl.
  • heteroaryl is monocyclic.
  • Alkyl groups are straight or branched chain and are, for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.
  • Alkoxy groups are straight or branched chain and are, for example, methoxy, ethoxy, n-propoxy, iso-propoxy or tert- butoxy.
  • Haloalkyl is preferably alkyl optionally substituted with 1, 2 or 3 chloro or fluoro atoms, and is, for example, CF 3 .
  • Cycloalkyl is mono- or bi-cyclic and is, for example, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl.
  • Arylalkyl is, for example, benzyl, 2-phenyleth-l-yl or 1-phenyleth-l-yl.
  • Heteroarylalkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or furylrnethyl.
  • a suitable salt of a compound of formula (I) includes a chloride, bromide, tosylate, mesylate, sulphate or phosphate salt.
  • the invention provides a compound of formula (I) wherein: R 1 is phenyl which is optionally substituted by halogen, C M alkyl, C M haloalkyl, CM alkoxy, C M haloalkoxy, nitro or cyano; R 2 , R 3 and R 4 are, independently, hydrogen or C M alkyl; R 5 is aryl, heteroaryl, aryl(C M )alkyl or heteroaryl(C M )alkyl; wherein the aryl and heteroaryl moieties of R 5 are optionally substituted by halogen, Ci- ⁇ alkyl (optionally substituted by halogen, C ⁇ _ 6 alkoxy or phenyl (itself optionally substituted by halogen, CM alkyl, C M alkoxy or CF 3 )), OR 6 , S(O) m R 7 , S(O) 2 NR 8 R 9 , NR 10 S(O) 2 R 1 C(O)R 12
  • X is (CH 2 ) n , where n is 1, 2, 3 or 4;
  • Y is a 2,4-, 2,5- or 3,5- linking 5-membered heteroaryl ring comprising 2 or 3 heteroatoms independently selected from the group comprising nitrogen, oxygen and sulphur, wherein Y is optionally substituted by C alkyl;
  • R 6 , R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are, independently, hydrogen or C ⁇ _ 6 alkyl (optionally substituted by C ⁇ -6 alkoxy (provided no acetal or aminal is formed) or phenyl (itself optionally substituted by halogen, C alkyl,
  • R 12 is hydrogen, C ⁇ . 6 alkyl (optionally substituted by C ⁇ . 6 alkoxy (provided no acetal is formed) or phenyl (itself optionally substituted by halogen, CM alkyl, C M alkoxy or CF 3 )) or C ⁇ -6 alkoxy (unsubstituted or mono-substituted by C ⁇ .
  • n is 2.
  • R 1 is phenyl optionally substituted by C M alkyl (such as methyl), C M alkoxy (such as methoxy) or halogen (such as chloro or fluoro).
  • the group R 1 can be phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5- difluorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro- 4-methoxyphenyl or 2-methyl-3-fluorophenyl.
  • the group R 1 is, for example, 3,4- dichlorophenyl or 3,4-difluorophenyl.
  • R 2 is hydrogen.
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 5 is C ⁇ _ 6 alkyl (such as methyl or propyl), C 3 . 8 cycloalkyl (such as cyclopropyl, cyclohexyl or bicyclo[2.2.1]heptyl), phenyl, monocyclic heteroaryl, benzyl or monocyclic heteroarylmethyl, wherein the phenyl and heteroaryl moieties of R 5 are optionally substituted by halogen (such as chloro or fluoro), C M alkyl (such as methyl and iso-propyl), C M alkoxy (such as methoxy), C M haloalkyl ' (such as CF 3 ), methylenedioxy, C(O)(C M alkyl) (such as acetyl), C thioalkyl (such as SCH 3 ), cyano, N(C M alkyl) 2 (such as N(CH 3 ) 2 ), NHC(O)(C M alkyl) (
  • R 5 is phenyl, monocyclic heteroaryl, benzyl or monocyclic heteroarylmethyl, wherein the phenyl and heteroaryl moieties of R 5 are optionally substituted by halogen (such as chloro or fluoro), C M alkyl (such as methyl and iso-propyl), C M alkoxy (such as methoxy), C M haloalkyl (such as CF 3 ), methylenedioxy, C(O)(CM alkyl) (such as acetyl), CM thioalkyl (such as SCH 3 ), cyano, N(CM alkyl) 2 (such as N(CH 3 ) 2 ), NHC(O)(CM alkyl) (such as NHC(O)CH 3 ), C(O)N(C M alkyl) 2 (such as C(O)N(CH 3 ) 2 ) or S(O) 2 (C M alkyl) (such as S(O) 2 (C M alkyl
  • R 5 is 2,4-difluorophenyl, 2-pyridyl, 3-pyridyl, 2- fluorophenyl, 2- chlorophenyl or 3-cyanophenyl.
  • Y is a 2,5-linked thiazolyl ring (optionally substituted with C alkyl, for example methyl), or a 3,5-linked 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl or 1,3,4-thiadiazolyl ring.
  • Y is 3,5-linked 1,2,4-oxadiazolyl or 2,5-linked thiazolyl.
  • the present invention provides a compound of formula (la):
  • a and B are (for example, independently) chloro or fluoro, and R 3 , n, R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (la'):
  • A, B, G and M are, independently, hydrogen, chloro, fluoro, C M alkyl (for example methyl) or C M alkoxy (for example methoxy), and R 3 , n, R 4 and R 5 are as defined above.
  • a and B are (for example, independently) chloro or fluoro, and R 3 , n, R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (lb'), wherein A, B, G and M are, independently, hydrogen, chloro, fluoro, C alkyl (for example methyl) or CM alkoxy (for example methoxy), and R 3 , n, R 4 and R 5 are as defined above.
  • a and B are (for example, independently) chloro or fluoro, and R 3 , n, R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (Ic'), wherein A, B, G and M are, independently, hydrogen, chloro, fluoro, C M alkyl (for example methyl) or C M alkoxy (for example methoxy), and R 3 , n, R 4 and R 5 are as defined above.
  • a and B are (for example, independently) chloro or fluoro, and R 3 , n, R 4 and R 5 are as defined above. .
  • the present invention provides a compound of formula (Id'), wherein A, B, G and M are, independently, hydrogen, chloro, fluoro, CM alkyl (for example methyl) or CM alkoxy (for example methoxy), and R 3 , n, R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (Ie): wherein A and B are (for example, independently) chloro or fluoro, and R 3 , n, R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (le 1 ), wherein A, B, G and M are, independently, hydrogen, chloro, fluoro, C alkyl (for example methyl) or C M alkoxy (for example methoxy), and R 3 , n, R 4 and R 5 are as defined above.
  • a and B are (for example, independently) chloro or fluoro, and R 3 , n, R 4 and R 5 are as defined above.
  • the present invention provides a compound of formula (If), wherein A, B, G and M are, independently, hydrogen, chloro, fluoro, C alkyl (for example methyl) or C M alkoxy (for example methoxy), and R 3 , n, R 4 and R 5 are as defined above.
  • Table II comprises 70 compounds of formula (lb'):
  • Table III comprises 70 compounds of formula (Ic'):
  • Table IN comprises 70 compounds of formula (Id'):
  • Table V comprises 70 compounds of formula (le'):
  • Table NI comprises 70 compounds of formula (If):
  • a compound of formula (I) wherein: Y is oxadiazolyl can be prepared as shown in Schemes 1 and 3 below; Y is 1,2,4-triazolyl can be prepared as shown in Scheme 2 below; Y is oxazole or thiazole can be prepared as shown in Schemes 4 (where Z is oxygen or sulphur), 5, 6, 7 or 11; Y is isoxazole can be prepared as shown in Schemes 8, 9 and 10; Y is pyrazole can be prepared as shown in Scheme 10 (or by using hydrazine in place of hyroxylamine, or the chlorohydrazone in place of the chlorooxime in Schemes 8 and 9); Y is 1 ,3,4-oxadiazole or thiadiazole can be prepared as shown in Scheme 12; Y is isothiazole can be prepared as shown in Schemes 13 and 14; and Y is 1,2,4-thiadiazole can be prepared as shown in Schemes 15 and 16.
  • R* is hydrogen or alkyl
  • PyBrOPTM is bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
  • HATU is O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU is O-Benzotriazol-l-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • EDCI is Ethyl dimethylaminopropyl carbodiimide hydrochloride
  • HOBT is 1 -hydroxybenzorriazole
  • DMAP is dimethylaminopyridine 4.
  • RT is room temperature
  • BuLi is a butyl lithium
  • the compounds of the invention can be prepared by coupling a compound of formula (II):
  • a suitable solvent such as N,N-dimethylformamide
  • a suitable coupling agent for example using PyBrOPTM; HATU; HBTU; EDCI/HOBT/DMAP
  • a compound of formula (I) wherein R 2 is hydrogen can be prepared by reacting a compound of formula (IN): with an aldehyde of formula R'CHO in a suitable solvent (such as N-methylpyrrolidinone) and in the presence of a suitable acid (such as acetic acid); and reducing the product so formed (with, for example, sodium triacetoxyborohydride).
  • a suitable solvent such as N-methylpyrrolidinone
  • a suitable acid such as acetic acid
  • a compound of formula (I) wherein Y is 1,3,4-oxadiazolyl and R 4 is hydrogen can be prepared by heating a compound of formula (V):
  • a suitable temperature such as in the range 50-100°C
  • a suitable solvent such as dimethylformamide
  • a suitable ring-closure chemical such as N- cyclohexylcarbodiimide, for example supported on a suitable polymer such as polystyrene
  • a compound of formula (V) can be prepared by reacting a compound of formula (VI):
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
  • the present invention provides processes for the preparation of compounds of formula (I), (la), (la*), (lb), (lb*), (Ic), (Ic"), (Id), (Id*), (le), (le*), (If) and (If).
  • the compounds of formula (I), (la), (la'), (lb), (lb'), (Ic), (Ic*), (Id), (Id'), (le), (le'), (If) and (If), or a salt thereof, a solvate thereof or a solvate of a salt thereof, have activity as pharmaceuticals, in particular as modulators of chemokine receptor activity. More particularly, the compounds have utility as modulators of the activity of chemokine receptor CCR3.
  • a further aspect of the invention involves the use of a compound of formula (I), (la), (la'), (lb), (lb'), (Ic), (Ic'), (Id), (Id'), (le), (le'), (If) or (If), or a salt thereof, a solvate thereof or a solvate of a salt thereof, in the treatment of conditions or diseases in which modulation of the CCR3 chemokine receptor activity is beneficial.
  • the compounds of the invention may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
  • AIDS Acquired Immunodeficiency Syndrome
  • obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper- responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhimtis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (bone and joints)
  • COPD chronic
  • the present invention provides a compound of formula (I), (la), (la'), (lb),
  • a salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore defined for use in therapy for example in the treatment of a chemokine mediated disease state (especially a CCR3 mediated disease state) in a mammal, such as man, such as in the treatment of a respiratory disease state (for example asthma and/or rhinitis).
  • a chemokine mediated disease state especially a CCR3 mediated disease state
  • a respiratory disease state for example asthma and/or rhinitis
  • the compounds of the invention, or a salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore defined, are especially useful in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; or rhinitis ⁇ including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ .
  • asthma such as bronchial, allergic, intrinsic, extrins
  • the present invention provides the use of a compound of formula
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the invention also provides a method of treating a CCR3 mediated disease state
  • a mammal such as man suffering from, or at risk of, said disease state, which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), (la), (la'), (lb), (lb*), (Ic), (Ic'), (Id), (Id'),
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • a compound of formula (I), (la), (la 1 ), (lb), (lb'), (Ic), (Ic'), (Id), (Id'), (le), (le 1 ), (If) or (If), or a salt thereof, a solvate thereof or a solvate of a salt thereof, may be used on its own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I), (la), (la'), (lb), (lb'), (Ic), (Ic'), (Id), (Id'), (le), (le'), (If) or (If), or a salt thereof, a solvate thereof or a solvate of a salt thereof, (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (la), (la'), (lb), (lb'), (Ic), (Ic'), (Id), (Id'), (le), (le'), (If) or (If), or a salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), (la), (la'), (lb), (lb'), (Ic), (Ic'), (Id), (Id'), (le), (le'), (If) or (If), or a salt thereof, a solvate • thereof or a solvate of a salt thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (for example to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, for example by oral administration in the form of tablets, capsules, syrups, powders, aerosols or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transderrnally.
  • the present invention provides a pharmaceutical combination comprising a compound of formula (I), (la), (la*), (lb), (lb*), (Ic), (Ic'), (Id), (Id'), (le), (le'), (If) or (If), or a salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore described, and a histamine antagonist, a steroid, a leukotriene modulator or an IL-5 receptor antibody.
  • Histamine antagonists include loratidine, desloratidine, fexofenadine, cetirizine, ebastine, astemizole, norastemizole, epinastine or efletirizine.
  • Steroids include budesonide, fluticasone, mometasone, rofleponide (such as rofleponide palmitate) or formoterol.
  • Leukotriene modulators include montelukast (such as in its sodium salt form), pranlukast, ZD4407 or zafirlukast.
  • EXAMPLE 1 This Example illustrates the preparation of 3-[5-(2-chloro-phenylamino)- [l,3,4]oxadiazol-2-yl]- N-[l-(3,4-dichloro-benzyl)-piperidin-4-yl]-propionamide (Compound No. 6 of Table I). a) N- [ 1 -(3 ,4-Dichlorobenzyl)-piperidin-4-yl] -3 -hydrazinocarbonyl-propionamide.
  • EXAMPLE 2 The present Example illustrates the preparation of 3-[5-(2-chloro-phenylamino)- [ 1 ,3 ,4]oxadiazol-2-yl]- N-[ 1 -(3 ,4-difluorobenzyl)-piperidin-4-yl]-propionamide (Compound No. 22 of Table I). a) N-[l-(3,4-Difluorobenzyl)-piperidin-4-yl]-3-hydrazinocarbonyl-propionamide
  • Isothiocyanato-benzene (0.1ml) and N-[l-(3,4-dichlorobenzyl)-piperidin-4-yl]-2- hydrazinocarbonyl-acetamide ( ⁇ .l ⁇ g) were stirred together in dimethylformamide (2ml) at ambient temperature for 2 hours.
  • AM resin 0.162g, Novabiochem, 2% DNB 1.57 mmol/g
  • ⁇ -cyclohexylcarbodiimide ⁇ -methyl polystyrene HL 0.19g, Novabiochem, 1.69 mmol/g
  • AM resin (0.35g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 135 mm. The mixture was filtered and methane sulphonic acid (lOO ⁇ l) was added and the solution was heated to 110°C for 4h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate; the organic phases were washed with water and then brine, then dried, filtered and evaporated.
  • Step 2 N-(l-benzylpiperidin-4-yl)-3- ⁇ 5-[(2,4-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ propanamide
  • Step 3 3- ⁇ 5-[(2,4-difluorophenyl)amino]-l,3,4-oxadiazol-2-yl ⁇ -N-piperidin-4- ylpropanamide
  • N-(l-Benzylpiperidin-4-yl)-3- ⁇ 5-[(2,4-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ propanamide (8.14g, 18.4mmol) was dissolved in ethanol and hydrogenated over a Pd/C catalyst at 3 bar until the reaction had gone to completion. The reaction mixture was filtered and the filtrate was evaporated to dryness, leaving an off-white solid which was triturated in ether, filtered and then dried in air to leave the subtitle compound (2.68g, 41%).
  • Step 4 N-(l-benzylpiperidin-4-yl)-3- ⁇ 5-[(2,4-difluorophenyl)amino]-l,3,4-oxadiazol-2- yl ⁇ propanamide
  • EXAMPLE 8 Pharmacological Analysis Calcium flux [Ca 2+ ]-_ assay a) Human eosinophils Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J Immunol. Methods, 1991, 145, 105-110).
  • the cells were resuspended (5xl0 6 ml "1 ) and loaded with 5 ⁇ M FLUO-3/AM + Pluronic F127 2.2 ⁇ l/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118mM, MgSO 4 0.8mM, glucose 5.5mM, Na 2 CO 3 8.5mM, KC1 5mM, HEPES 20mM, CaCi2 1.8mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200g for 5min and resuspended in LKS at 2.5x10 6 ml "1 .
  • LKS low potassium solution
  • the cells were then transferred to 96 well FLIPR plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 ⁇ M fibronectin for two hours) at lOOml/well.
  • the plate was centrifuged at 200g for 5min and the cells were washed twice with LKS (200 ⁇ l; room temperature).
  • a compound of the Examples was pre-dissolved in dimethylsulphoxide and added to a final concentration of 0.1%(v/v) dimethylsulphoxide.
  • Human monocytes were isolated from EDTA anticoagulated peripheral blood as previously described (Cunoosamy & Holbrook, J. Leukocyte Biology, 1998, S2, 13). Cells were resuspended (5xl0 6 ml "1 ) in LKS and loaded with 5 ⁇ M FLUO-3/AM + Pluronic F127 2.2 ⁇ l/ml (Molecular Probes) for one hour at room temperature. After loading, cells were centrifuged at 200g for 5min and resuspended in LKS at 0.5x10 6 ml "1 . The cells were then transferred to 96 well FLIPR plates (Costar). To each well lOO ⁇ l of cells were added at a concentration of 0.5x10 6 ml '1 .
  • the plates were centrifuged (200g; 5 rnins; room temperature) to allow the cells to adhere. After centrifugation the cells were washed twice with LKS (200 ⁇ l; room temperature).
  • the compounds of the Examples were found to be antagonists of the eotaxin mediated [Ca 2+ ] ⁇ in human eosinophils and/or antagonists of the MlP-l ⁇ mediated [Ca 2+ ]i in human monocytes.
  • Human eosinophil chemotaxis Human eosinophil chemotaxis
  • Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended at lOxlO 6 ml "1 in RPMI containing 200 IU/ml penicillin, 200 ⁇ g/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.
  • Eosinophils 700 ⁇ l were pre-incubated for 15 mins at 37° C with 7 ⁇ l of either vehicle or compound (lOOx required final concentration in 10% dimethylsulphoxide).
  • the chemotaxis plate (ChemoTx, 3 ⁇ m pore, Neuroprobe) was loaded by adding 28 ⁇ l of a concentration of eotaxin (0.1 to lOOnM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate.
  • the filter was then placed over the wells and 25 ⁇ l of eosinophil suspension were added to the top of the filter.
  • the plate was incubated for 1 hr at 37° C in a humidified incubator with a 95% air/5% CO 2 atmosphere to allow chemotaxis.
  • the medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded.
  • the filter was washed once with phosphate buffered saline (PBS) containing.5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300xg for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar).
  • PBS phosphate buffered saline
  • the pelleted cells were lysed by the addition of 28 ⁇ l of PBS containing 0.5% Triton xlOO followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant. Certain compounds of the Examples were found to be- antagonists of the eotaxin mediated human eosinophil chemotaxis.

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DE60201259D1 (de) 2004-10-21
JP2004518742A (ja) 2004-06-24
GB0104050D0 (en) 2001-04-04
WO2002066460A1 (en) 2002-08-29
ATE276246T1 (de) 2004-10-15
DE60201259T2 (de) 2005-09-29
US6958350B2 (en) 2005-10-25
EP1363902B1 (de) 2004-09-15
US20040102483A1 (en) 2004-05-27

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